The long-term goal of this project is to understand the significance of cyclooxygenase (COX) metabolites in the initiation and expression of long-term synaptic plasticity and neuronal survival. The bioactive lipids, arachidonic acid (AA) and platelet-activating factor (PAF), and phospholipase A (PLA), the enzyme that generates them, have been implicated in expression or maintenance of long-term potentiation (LTP) in the hippocampus. However, little is known about the role of prostaglandins (PGs) in synaptic plasticity. PGs are synthesized from AA via COX. Two COX isoforms, COX-1 and COX-2, have been identified. Neuronal COX-2 expression is rapidly induced by ischemia, seizures and NMDA-dependent synaptic activity. Further evidence shows that COX-2 is expressed in postsynaptic dendritic spines where active synapses are present. Our preliminary data indicate that selective COX-2 inhibitors, but not COX- 1 inhibitors, reduce membrane excitability and high-frequency stimulation (HFS)-induced LTP in hippocampal neurons and that application of PGE2 rescues COX-2 inhibitor-induced suppressions of LTP induction and membrane excitability. This information implicates PGs synthetized by COX-2 for an important role in processing and storage of synaptic information. Recent evidence indicates that the back-propagating dendritic action potential is a critical element in the induction of long-term synaptic plasticity in hippocampal pyramidal neurons. Thus, we hypothesize that synaptic activity-dependent synthesis of PGs catalyzed by COX-2 regulates the probability of LTP induction by modifying dendritic excitability of hippocampal pyramidal neurons. Four specific aims are proposed to test predictions of this hypothesis: 1) synaptic activity-dependent synthesis of PG(s) by COX-2 increases dendritic excitability; 2) postsynaptic synthesis of PGs by COX-2 is activity-dependent; 3) localized application of AA and PG(s) will mimic the effect of coincident synaptic activity; and 4) COX-2 synthesized PG(s) regulates membrane excitability and long-term synaptic activity in hippocampal pyramidal neurons. The proposed project will further our understanding of hippocampal synaptic plasticity and will also contribute towards the understanding of the pathophysiology of neurological disorders such as epilepsy, stroke and neurodegenerative diseases.